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Cannabinoids


General information

Cannabis is the abbreviated name for the hemp plant Cannabis sativa . The common names for cannabis include marijuana, grass, and weed. Other names for cannabis refer to particular strains; they include bhang and ganja. The most potent forms of cannabis come from the flowering tops of the plants or from the dried resinous exudate of the leaves, and are referred to as hashish or hash. Cannabis sativa contains more than 450 substances and only a few of the main active cannabinoids have been evaluated.

Cannabis is the most commonly used illicit drug. In 2001, 83 million Americans and 37% of those aged 12 and older had tried marijuana [ ].The long history of marijuana use both as a recreational drug and as a herbal medicine for centuries has been reviewed [ ].

In different Western countries the possible therapeutic use of cannabinoids as antiemetics in patients with cancer or in patients with multiple sclerosis has been debated, because of the prohibition of cannabis, and has polarized opinion about the seriousness of its adverse effects [ , ].

Pharmacology

The primary active component of cannabis is Δ9-tetrahydrocannabinol (THC), which is responsible for the greater part of the pharmacological effects of the cannabis complex. Δ8-THC is also active. However, the cannabis plant contains more than 400 chemicals, of which some 60 are chemically related to Δ9-THC, and it is evident that the exact proportions in which these are present can vary considerably, depending on the way in which the material has been harvested and prepared. In man, Δ9-THC is rapidly converted to 11-hydroxy-Δ9-THC [ ], a metabolite that is active in the central nervous system. A specific receptor for the cannabinols has been identified; it is a member of the G-protein-linked family of receptors [ ]. The cannabinoid receptor is linked to the inhibitory G-protein, which is linked to adenyl cyclase in an inhibitory fashion [ ]. The cannabinoid receptor is found in highest concentrations in the basal ganglia, the hippocampus, and the cerebellum, with lower concentrations in the cerebral cortex.

When cannabis is smoked, usually in a cigarette with tobacco, the euphoric and relaxant effects occur within minutes, reach a maximum in about 30 minutes, and last up to 4 hours. Some of the motor and cognitive effects can persist for 5–12 hours. Cannabis can also be taken orally, in foods such as cakes (for example “space cake”) or sweetmeats (for example hashish fudge) [ ].

Many variables affect the psychoactive properties of cannabis, including the potency of the cannabis used, the route of administration, the smoking technique, the dose, the setting, the user’s past experience, the user’s expectations, and the user’s biological vulnerability to the effects of the drug.

In research on the effects of cannabinoids the routes of administration include smoking a plant-derived cigarette, oral dronabinol (synthetic delta 9-tetrahydrocannabinol, THC), or intravenous THC. Each method has specific characteristics: cigarettes deliver a wide range of dosages, dronabinol has a slower onset of action and lower potency, and intravenous THC offers precise dose and timing [ ]. Careful screening of subjects’ medical backgrounds and status and close monitoring during research participation are essential.

Animal and in vitro toxicology

Δ9-tetrahydrocannabinol, the active component in herbal cannabis, is very safe. Laboratory animals (rats, mice, dogs, monkeys) can tolerate doses of up to 1000 mg/kg, equivalent to some 5000 times the human intoxicant dose. Despite the widespread illicit use of cannabis, there are very few, if any, instances of deaths from overdose [ ].

Long-term toxicology studies with THC were carried out by the National Institute of Mental Health in the late 1960s [ ]. These included a 90-day study with a 30-day recovery period in both rats and monkeys and involved not only Δ9-THC but also Δ8-THC and a crude extract of marijuana. Doses of cannabis or cannabinoids in the range 50–500 mg/kg caused reduced food intake and lower body weight. All three substances initially depressed behavior, but later the animals became more active and were irritable or aggressive. At the end of the study the weights of the ovaries, uterus, prostate, and spleen were reduced and the weight of the adrenal glands was increased. The behavioral and organ changes were similar in monkeys, but less severe than those seen in rats. Further studies were carried out to assess the damage that might be done to the developing fetus by exposure to cannabis or cannabinoids during pregnancy. Treatment of pregnant rabbits with THC at doses up to 5 mg/kg had no effect on birth weight and did not cause any abnormalities in the offspring [ ].

A similarly detailed toxicology study was carried out with THC by the National Institute of Environmental Health Sciences in the USA, in response to a request from the National Cancer Institute [ ]. Rats and mice were given THC up to 500 mg/kg five times a week for 13 weeks; some were followed for a period of recovery over 9 weeks. By the end of the study more than half of the rats treated with the highest dose (500 mg/kg) had died, but all of the remaining animals appeared to be healthy, although in both species the higher doses caused lethargy and increased aggressiveness. The THC-treated animals ate less food and their body weights were consequently significantly lower than those of untreated controls at the end of the treatment period, but returned to normal during recovery. During this period the animals were sensitive to touch and some had convulsions. There was a trend towards reduced uterine and testicular weights.

In further studies rats were treated with doses of THC up to 50 mg/kg and mice with up to 500 mg/kg five times a week for 2 years in a standard carcinogenicity test [ ]. After 2 years, more treated animals had survived than controls, probably because the treated animals ate less and had lower body weights. The treated animals also had a significantly lower incidence of the various cancers normally seen in aged rodents in testes, pancreas, pituitary gland, mammary glands, liver, and uterus. Although there was an increased incidence of precancerous changes in the thyroid gland in both species and in the mouse ovary after one dose (125 mg/kg), these changes were not dose-related. The conclusion was that there was “no evidence of carcinogenic activity of THC at doses up to 50 mg/kg.” This was also supported by the failure to detect any genetic toxicity in other tests designed to identify drugs capable of causing chromosomal damage. For example, THC was negative in the so-called “Ames test,” in which bacteria are exposed to very high concentrations of a drug to see whether it causes mutations. In another test, hamster ovary cells were exposed to high concentrations of the drug in tissue culture; there were no effects on cell division that might suggest chromosomal damage.

By any standards, THC must be considered to be very safe, both acutely and during long-term exposure. This probably partly reflects the fact that cannabinoid receptors are virtually absent from those regions at the base of the brain that are responsible for such vital functions as breathing and blood pressure control. The available animal data are more than adequate to justify its approval as a human medicine, and indeed it has been approved by the FDA for certain limited therapeutic indications (generic name = dronabinol) [ ].

Respiratory

There have been several attempts to address this question by exposing laboratory animals to cannabis smoke. After such exposure on a daily basis for periods of up to 30 months, extensive damage has been observed in the lungs of rats [ ], dogs [ ], and monkeys [ ], but it is very difficult to extrapolate these findings to man, as it is difficult or impossible to imitate human exposure to cannabis smoke in any animal model.

Nervous system

Animal studies on neurotoxicity have yielded conflicting results. Treatment of rats with high doses of THC given orally for 3 months [ ] or subcutaneously for 8 months [ ] produced neural damage in the hippocampal CA3 zone, with shrunken neurons, reduced synaptic density, and loss of cells. But in perhaps the most severe test of all, rats and mice treated on 5 days each week for 2 years had no histopathological changes in the brain, even after 50 mg/kg/day (rats) or 250 mg/kg/day (mice) [ ]. Although claims were made that exposure of a small number of rhesus monkeys to cannabis smoke led to ultrastructural changes in the septum and hippocampus [ , ], subsequent larger-scale studies failed to show any cannabis-induced histopathology in monkey brain [ ].

Studies of the effects of cannabinoids on neurons in vitro have also yielded inconsistent results. Exposure of rat cortical neurons to THC shortened their survival: twice as many cells were dead after exposure to THC 5 μmol/l for 2 hours than in control cultures [ ]. Concentrations of THC as low as 0.1 μmol/l had a significant effect. The effects of THC were accompanied by release of cytochrome c , activation of caspase-3, and DNA fragmentation, suggesting an apoptotic mechanism. All of the effects of THC could be blocked by the antagonist AM-251 or by pertussis toxin, suggesting that they were mediated through CB1 receptors. Toxic effects of THC have also been reported in hippocampal neurons in culture, with 50% cell death after exposure to THC 10 μmol/l for 2 hours or 1 μmol/l for 5 days [ ]. The antagonist rimonabant blocked these effects, but pertussis toxin did not. The authors proposed a toxic mechanism involving arachidonic acid release and the formation of free radicals. On the other hand, other authors have failed to observe any damage in rat cortical neurons exposed for up to 15 days to THC 1 mmol/l, although they found that this concentration killed rat C6 glioma cells, human astrocytoma U373MG cells, and mouse neuroblastoma N18TG12 cells [ ]. In a remarkable study, injection of THC into solid tumors of C6 glioma in rodent brain led to increased survival times, and there was complete eradication of the tumors in 20–35% of the treated animals [ ]. A stable analogue of anandamide also produced a drastic reduction in the tumor volume of a rat thyroid epithelial cell line transformed by the KRAS oncogene, implanted in nude mice [ ]. The antiproliferative effect of cannabinoids has suggested a potential use for such drugs in cancer treatment [ ].

Some authors have reported neuroprotective actions of cannabinoids. WIN55212-2 reduced cerebral damage in rat hippocampus or cerebral cortex after global ischemia or focal ischemia in vivo [ ]. The endocannabinoid 2AG protected against damage elicited by closed head injury in mouse brain, and the protective effects were blocked by rimonabant [ ]. THC had a similar effect in vivo in protecting against damage elicited by ouabain [ ]. Rat hippocampal neurons in tissue culture were protected against glutamate-mediated damage by low concentrations of WIN55212-2 or CP-55940, and these effects were mediated through CB1 receptors [ ]. But not all of these effects seem to require mediation by cannabinoid receptors. The protective effects of WIN55212-2 did not require either CB1 or CB2 cannabinoid receptors in cortical neurons exposed to hypoxia [ ], and there were similar findings for the protective actions of anandamide and 2-AG in cortical neuronal cultures [ ]. Both THC and cannabidiol, which is not active at cannabinoid receptors, protected rat cortical neurons against glutamate toxicity [ ] and these effects were also independent of CB1 receptors. The authors suggested that the protective effects of THC might be due to the antioxidant properties of these polyphenolic molecules, which have redox potentials higher than those of known antioxidants (for example ascorbic acid).

Pregnancy

In animals, THC can cause spontaneous abortion, low birth weight, and physical deformities [ ]. However, these were only seen after treatment with extremely high doses of THC (50–150 times higher than human doses), and only in rodents and not in monkeys.

Tolerance and dependence

Many animal studies have shown that tolerance develops to most of the behavioral and physiological effects of THC [ ]. Dependence on cannabinoids in animals is clearly observable, because of the availability of CB1 receptor antagonists, which can be used to precipitate withdrawal. Thus, a behavioral withdrawal syndrome was precipitated by rimonabant in rats treated for only 4 days with THC in doses as low as 0.5–4.0 mg/kg/day [ ]. The syndrome included scratching, face rubbing, licking, wet dog shakes, arched back, and ptosis, many of the signs that are seen in rats undergoing opiate withdrawal. Similar withdrawal signs occurred when rats treated chronically with the synthetic cannabinoid CP-55940 were given rimonabant [ ]. Rimonabant-induced withdrawal after 2 weeks of treatment of rats with the cannabinoid HU-120 was accompanied by a marked increase in release of the stress-related neuropeptide corticotropin-releasing factor in the amygdala, a result that also occurred in animals undergoing heroin withdrawal [ ]. An electrophysiological study showed that precipitated withdrawal was also associated with reduced firing of dopamine neurons in the ventral tegmental area of rat brain [ ].

These data clearly show that chronic administration of cannabinoids leads to adaptive changes in the brain, some of which are similar to those seen with other drugs of dependence. The ability of THC to cause selective release of dopamine from the nucleus accumbens [ ] also suggests some similarity between THC and other drugs in this category.

Furthermore, although many earlier attempts to obtain reliable self-administration behavior with THC were unsuccessful [ ], some success has been obtained recently. Squirrel monkeys were trained to self-administer low doses of THC (2 micrograms/kg per injection), but only after the animals had first been trained to self-administer cocaine [ ]. THC is difficult to administer intravenously, but these authors succeeded, perhaps in part because they used doses comparable to those to which human cannabis users are exposed, and because the potent synthetic cannabinoids are far more water-soluble than THC, which makes intravenous administration easier. Mice could be trained to self-administer intravenous WIN55212-2, but CB1 receptor knockout animals could not [ ].

Another way of demonstrating the rewarding effects of drugs in animals is the conditioned place preference paradigm, in which an animal learns to approach an environment in which it has previously received a rewarding stimulus. Rats had a positive THC place preference after doses as low as 1 mg/kg [ ].

Some studies have suggested that there may be links between the development of dependence to cannabinoids and to opiates [ ]. Some of the behavioral signs of rimonabant-induced withdrawal in THC-treated rats can be mimicked by the opiate antagonist naloxone [ ]. Conversely, the withdrawal syndrome precipitated by naloxone in morphine-dependent mice can be partly relieved by THC [ ] or endocannabinoids [ ]. Rats treated chronically with the cannabinoid WIN55212-2 became sensitized to the behavioral effects of heroin [ ]. Such interactions can also be demonstrated acutely. Synergy between cannabinoids and opiate analgesics has been described above. THC also facilitated the antinociceptive effects of RB 101, an inhibitor of enkephalin inactivation, and acute administration of THC caused increased release of Met-enkephalin into microdialysis probes placed into the rat nucleus accumbens [ ].

The availability of receptor knockout animals has also helped to illustrate cannabinoid–opioid interactions. CB1 receptor knockout mice had greatly reduced morphine self-administration behavior and less severe naloxone-induced withdrawal signs than wild type animals, although the antinociceptive actions of morphine were unaffected in the knockout animals [ ]. The rimonabant-precipitated withdrawal syndrome in THC-treated mice was significantly attenuated in animals with knockout of the pro-enkephalin gene [ ]. Knockout of the μ opioid (OP3) receptor also reduced rimonabant-induced withdrawal signs in THC-treated mice, and there was an attenuated naloxone withdrawal syndrome in morphine-dependent CB1 knockout mice [ , ].

These findings clearly point to interactions between the endogenous cannabinoid and opioid systems in the CNS, although the neuronal circuitry involved is unknown. Whether this is relevant to the so-called “gateway” theory is unclear. In the US National Household Survey of Drug Abuse, respondents aged 22 years or over who had started to use cannabis before the age of 21 years were 24 times more likely than non-cannabis users to begin using hard drugs [ ]. However, in the same survey the proportion of cannabis users who progressed to heroin or cocaine use was very small (2% or less). Mathematical modeling using the Monte Carlo method suggested that the association between cannabis use and hard drug use need not be causal, but could relate to some common predisposing factor, for example “drug-use propensity” [ ].

Tumorigenicity

THC does not appear to be carcinogenic, but there is plenty of evidence that the tar derived from cannabis smoke is. Bacteria exposed to cannabis tar develop mutations in the standard Ames test for carcinogenicity [ ], and hamster lung cells in tissue culture develop accelerated malignant transformations within 3–6 months of exposure to tobacco or cannabis smoke [ ].

Three different associations of cannabinoids with cancer have been discussed [ ]. Firstly, there is a possible direct carcinogenic effect. In in vitro studies and in mice tetrahydrocannabinol alone does not seem to be carcinogenic or mutagenic. However, cannabis smoke is both carcinogenic and mutagenic and contains similar carcinogens to those in tobacco smoke. Cannabis is possibly linked to digestive and respiratory system cancers. Case reports support this association but epidemiological cohort studies and case-control studies have provided conflicting evidence. Secondly, there is conflicting evidence on the beneficial effects of tetrahydrocannabinol and other cannabinoids in patients with cancer. In some in vitro and in vivo studies, tetrahydrocannabinol and synthetic cannabinoids had antineoplastic effects, but in others tetrahydrocannabinol had a negative effect on the immune system. Thirdly, cannabis may palliate some of the symptoms and adverse effects of cancer. Cannabis may improve appetite, reduce nausea and vomiting, and alleviate moderate neuropathic pain in patients with cancer. The authors defined the challenge for the medical use of cannabinoids as the development of safe, effective, and therapeutic methods of using it that are devoid of the adverse psychoactive effects. Lastly, they discussed the possible associations between cannabis smoking and tumors of the prostate and brain, noting the need for larger, controlled studies.

General adverse effects and adverse reactions in humans

The evidence related to the adverse effects of acute and chronic use of cannabis has been summarized [ ]. The effects of acute usage include anxiety, impaired attention, and increased risk of psychotic symptoms. Probable risks of chronic cannabis consumption include bronchitis and subtle impairments of attention and memory.

Adverse reactions to cannabis can be considered under two main headings, reflecting psychoactive and autonomic effects, in addition to which there are direct toxic effects. The most frequently reported psychoactive effects include enhanced sensory perception (for example a heightened appreciation of color and sound). Cannabis intoxication commonly heightens the user’s sensitivity to other external stimuli as well, but subjectively slows the appreciation of time. In high doses, users may also experience depersonalization and derealization. Various forms of psychomotor performance, including driving, are significantly impaired for 8–12 hours after using cannabis. The most serious possible consequence of cannabis use is a road accident if a user drives while intoxicated.

Adverse reactions have been reported at relatively low doses and principally affect the psyche, leading to anxiety states, panic reactions, restlessness, hallucinations, fear, confusion, and rarely toxic psychosis. These reactions appear to be reversible [ ]. Ingestion of cake containing cannabis by people who seldom use or have never used cannabis before can result in mental changes, including confusion, anxiety, loss of logical thinking, fits of laughter, hallucinations, hypertension, and/or paranoid psychosis, which can last as long as 8 hours.

The autonomic effects of cannabis lead to tachycardia, peripheral vasodilatation, conjunctival congestion, hyperthermia, bronchodilatation, dry mouth, nystagmus, tremor, ataxia, hypotension, nausea, and vomiting, that is a spectrum of effects that closely resembles the consequences of overdosage with anticholinergic agents. Some individuals have sleep disturbances. Increased appetite and dry mouth are other common effects of cannabis intoxication.

Hypersensitivity reactions are rare, but a few have been reported after inhalation. Delayed hypersensitivity reactions, particularly affecting vascular tissue, have been recorded with chronic systemic administration. Tumor-inducing effects are difficult to attribute to cannabis alone. Animal studies have shown neoplastic pulmonary lesions superimposed on chronic inflammation, but such pathology may be primarily associated with the “tar” produced by burning marijuana. The most serious potential adverse effects of cannabis use come from the inhalation of the same carcinogenic hydrocarbons that are present in tobacco, and some data suggest that heavy cannabis users are at risk of chronic respiratory diseases and lung cancer.

Drug studies

Observational studies

In an open trial the safety, tolerability, dose range, and efficacy of the whole-plant extracts of Cannabis sativa were evaluated in 15 patients with advanced multiple sclerosis and refractory lower urinary tract symptoms [ ]. The patients took extracts containing delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD; 2.5 mg per spray) for 8 weeks followed by THC only for a further 8 weeks. Urinary urgency, the number and volume of incontinence episodes, frequency, and nocturia all reduced significantly after treatment with both extracts. Patients’ own assessments of pain, spasticity, and quality of sleep improved significantly, and the improvement in pain continued for up to a median of 35 weeks. Most of the patients had symptoms of intoxication, such as mild drowsiness, disorientation, and altered time perception, during the dose titration period. Three had single short-lived hallucinations that did not occur when the dose was reduced. All complained of a worsening of dry mouth that was already present from other treatments and two complained of mouth soreness at the site of drug administration.

Of 220 patients with multiple sclerosis in Halifax, Canada 72 (36%) reported ever having used cannabis [ ]. Ever use of cannabis for medicinal purposes was associated with male sex, the use of tobacco, and recreational use of cannabis. Of the 34 medicinal cannabis users, 10 reported mild, 8 moderate and 1 strong adverse effects; none reported severe adverse effects. The most common adverse effects were feeling “high” (n = 24), drowsiness [ ], dry mouth [ ], paranoia [ ], anxiety [ ], and palpitation [ ].

Placebo-controlled studies

Cannabis has been used to treat many medical conditions, especially those involving pain and inflammation. Many studies with improved designs and larger sample sizes are providing preliminary data of efficacy and safety in conditions such as multiple sclerosis and chronic pain syndromes.

The effects of oral cannabinoids (dronabinol or Cannabis sativa plant extract) in relieving pain and muscle spasticity have been studied in 16 patients with multiple sclerosis (mean age 46 years, mean duration of disease 15 years) in a double-blind, placebo-controlled, crossover study [ ]. The initial dose was 2.5 mg bd, increasing to 5 mg bd after 2 weeks if the dose was well tolerated. The plant extract was more likely to cause adverse events; five patients had increased spasticity and one rated an adverse event of acute psychosis as severe. All physical measures were in the reference ranges. There were no significant differences in any measure of efficacy score that would indicate a therapeutic benefit of cannabinoids. This study is the largest and longest of its kind, but the authors acknowledged some possible shortcomings. The route of administration could affect subjective ratings, since the gastrointestinal tract is a much slower and more inefficient route than the lungs. Another possibility is that the dose was too small to have the desired therapeutic effects.

In a parallel group, double-blind, randomized, placebo-controlled study undertaken at three sites in 160 patients with multiple sclerosis a cannabis-based medicinal extract containing equal amounts of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) at doses of 2.5–120 mg of each daily in divided doses for 6 weeks, spasticity scores were significantly improved by cannabis [ ]. However, when the changes in symptoms were measured using the Primary Symptoms Scale, there were no significant differences between cannabis and placebo. The main adverse events were dizziness (33%), local discomfort at the site of application (26%), fatigue (15%), disturbance in attention (8.8%), disorientation (7.5%), a feeling of intoxication (5%), and mouth ulcers (5%).

In a randomized, double-blind, placebo-controlled, crossover trial the effect of the synthetic delta-9-tetrahydrocannabinol dronabinol on central neuropathic pain was evaluated in 24 patients with multiple sclerosis [ ]. Oral dronabinol reduced central pain. Adverse events were reported by 96% of the patients compared with 46% during placebo treatment. They were more common during the first week of treatment. The most common adverse events during dronabinol treatment were dizziness (58%), tiredness (42%), headache (25%), myalgia (25%), and muscle weakness (13%). There was increased tolerance to the adverse effects over the course of treatment and with dosage adjustments.

Three cannabis-based medicinal extracts in sublingual form recently became available for use against pain. In a randomized, double-blind, placebo-controlled, crossover study for 12 weeks in 34 patients with chronic neuropathic pain THC extracts were effective in symptom control [ ]. Drowsiness and euphoria/dysphoria were common in the first 2 weeks. Dizziness was less of a problem. Anxiety and panic were infrequent but occurred during the run-in period. Dry mouth was the most common complaint.

Organs and systems

Cardiovascular

Marijuana has several effects on the cardiovascular system, and can increase resting heart rate and supine blood pressure and cause postural hypotension. It is associated with an increase in myocardial oxygen demand and a decrease in oxygen supply. Peripheral vasodilatation, with increased blood flow, orthostatic hypotension, and tachycardia, can occur with normal recreational doses of cannabis. High doses of THC taken intravenously have often been associated with ventricular extra beats, a shortened PR interval, and reduced T wave amplitude, to which tolerance readily develops and which are reversible on withdrawal. While the other cardiovascular effects tend to decrease in chronic smokers, the degree of tachycardia continues to be exaggerated with exercise, as shown by bicycle ergometry.

Hypotension

Postural syncope after marijuana use has been studied in 29 marijuana-experienced volunteers, using transcranial Doppler to measure cerebral blood velocity in the middle cerebral artery in response to postural changes [ ]. They were required to abstain from marijuana and other drugs for 2 weeks before the assessment, as confirmed by urine drug screening. They were then given marijuana, tetrahydrocannabinol, or placebo and lying and standing measurements were made. When marijuana or tetrahydrocannabinol was administered, 48% reported a dizziness rating of three or four and had significant falls in standing cerebral blood velocity, mean arterial blood pressure, and systolic blood pressure. Eight subjects were so dizzy that they had to be supported. The authors suggested that marijuana interferes with the protective mechanisms that maintain standing blood pressure and cerebral blood velocity. All but one of the subjects who took marijuana or tetrahydrocannabinol reported some degree of dizziness. Women tended to be dizzier. As the postural dizziness was significant and unrelated to plasma concentrations of tetrahydrocannabinol or other indices, the authors raised concerns about marijuana use in those who are medically compromised or elderly.

Activation of cannabinoid CB1 receptors by cannabis or delta-9 tetrahydrocannabinol (THC) is associated with reduced blood pressure. The effects of rimonabant, a CB1 receptor antagonist, on blood pressure have been reported in 63 male cannabis smokers [ ]. The smokers were assigned to eight groups and were pretreated with oral rimonabant (1, 3, 10, 30, 90 mg) or placebo. They smoked active (2.64% THC) or placebo marijuana cigarettes 2 and 6 hours after rimonabant. Cannabis alone had no consistent effect on blood pressure but 22% reported hypotensive symptoms (dizziness, lightheadedness) as did 20–33% of rimonabant recipients (1, 3, or 10 mg). Subjects who had symptomatic hypotension had higher mean peak plasma THC concentrations than those who did not. Rimonabant had a dose-dependent effect on the hypotensive response to cannabis. Subjects receiving the two highest doses, 30 and 90 mg, did not have symptomatic hypotension.

Myocardial ischemia

Marijuana use is most popular among young adults (18–25 years old). However, with a generation of post-1960s smokers growing older, the use of marijuana in the age group that is prone to coronary artery disease has increased. The cardiovascular effects may present a risk to those with cardiovascular disorders, but in adults with normal cardiovascular function there is no evidence of permanent damage associated with marijuana [ , , ], and it is not known whether marijuana can precipitate myocardial infarction, although mixed use of tobacco and cannabis make the evaluation of the effects of cannabis very difficult.

Investigators in the Determinants of Myocardial Infarction Onset Study have reported that smoking marijuana is a rare trigger of acute myocardial infarction [ ]. Interviews of 3882 patients (1258 women) were conducted on an average of 4 days after infarction. Reported use of marijuana in the hour preceding the first symptoms of myocardial infarction was compared with use in matched controls. Among the patients, 124 reported smoking marijuana in the previous year, 37 within 24 hours, and 9 within 1 hour of cardiac symptoms. The risk of myocardial infarction was increased 4.8 times over baseline in the 60 minutes after marijuana use and then fell rapidly. The authors emphasized that in a majority of cases, the mechanism that triggered the onset of myocardial infarction involved a ruptured atherosclerotic plaque secondary to hemodynamic stress. It was not clear whether marijuana has direct or indirect hemodynamic effects sufficient to cause plaque rupture.

  • Two young men, aged 18 and 30 years, developed retrosternal pain with shortness of breath, attributed to acute coronary syndrome [ ]. Each had smoked marijuana and tobacco and admitted to intravenous drug use. Urine toxicology was positive for tetrahydrocannabinol. Aspartate transaminase and creatine kinase activities and troponin-I and C-reactive protein concentrations were raised. Echocardiography in the first patient showed hypokinesia of the posterior and inferior walls and in the second hypokinesia of the basal segment of the anterolateral wall. Coronary angiography showed normal coronary anatomy with coronary artery spasm. Genetic testing for three common genetic polymorphisms predisposing to acute coronary syndrome was negative.

The authors suggested that marijuana had increased the blood carboxyhemoglobin concentration, leading to reduced oxygen transport capacity, increased oxygen demand, and reduced oxygen supply.

Two other cases have been reported [ ].

  • A 48-year-old man, a chronic user of cannabis who had had coronary artery bypass grafting 10 years before and recurrent angina over the past 18 months, developed chest pain. An electrocardiogram showed intermittent resting ST segment changes and coronary angiography showed that of the three previous grafts, only one was still patent. There was also sub-total occlusion of a stent in the left main stem. After 24 hours he had a cardiac arrest while smoking cannabis and had multiple episodes of ventricular fibrillation, requiring both electrical and pharmacological cardioversion. He then underwent urgent percutaneous coronary intervention which involved stenting of his left main stem. He eventually stabilized and recovered for discharge 11 weeks later.

  • A 22-year-old man had two episodes of tight central chest pain with shortness of breath after smoking cannabis. He had been a regular marijuana smoker since his mid-teens and had used more potent and larger amounts during the previous 2 weeks. An electrocardiogram showed ST segment elevation in leads V1–5, with reciprocal ST segment depression in the inferior limb leads. A provisional diagnosis of acute myocardial infarction was made. Thrombolysis was performed, but the electrocardiographic changes continued to evolve. Angiography showed an atheromatous plaque in the left anterior descending artery which was dilated and stented. There was early diffuse disease in the cardiac vessels.

The authors suggested that in the first case ventricular fibrillation had been caused by increased myocardial oxygen demand in the presence of long-standing coronary artery disease. In the second case, they speculated that chronic cannabis use may have contributed to the unexpectedly severe coronary artery disease in a young patient with few risk factors.

Coronary no-flow and ventricular tachycardia after habitual marijuana use has been reported [ ].

In one case acute myocardial infarction was an outcome of inherited thrombophilia and cannabis smoking [ ].

  • A 24-year old man developed severe chest pain, which radiated to the arms and back for 4 hours. He had a 16 cigarette pack-year habit. There was ST segment elevation in leads V2–6, with reciprocal ST segment depression in II, III, and aVF. Troponin-T (18 ng/ml) and creatine kinase activity (7266 IU/l) were both raised. An anterolateral myocardial infarction was diagnosed. He was given clopidogrel, aspirin, heparin, and streptokinase. A stent was inserted at coronary angiography. Drug screening was positive for THC. Genetic testing revealed a hypercoagulable state with a combination of factor V Leiden mutation and the methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphism.

In this case, the increased risk of coronary artery thrombosis was inherited and smoking may have predisposed to coronary spasm and subsequent thrombosis.

Arteritis

Progressive arteritis associated with cannabis use has been reported [ ].

  • A 38-year-old Afro-Caribbean man was admitted after 3 months of severe constant ischemic pain and numbness affecting the right foot. The pain was worse at night. He also had intermittent claudication after walking 100 yards. He had a chronic history of smoking cannabis about 1 ounce/day, mixed with tobacco in the early years of usage. However, at the time of admission, he had not used tobacco in any form for over 10 years. He had patchy necrosis and ulceration of the toes and impalpable pulses in the right foot. The serum cotinine concentrations were consistent with those found in non-smokers of tobacco. Angiography of his leg was highly suggestive of Buerger’s disease (thromboangiitis obliterans).

Remarkably, this patient, despite having abstained from tobacco for more than 10 years, developed a progressive arteritis leading to ischemic changes. While arterial pathology with cannabis has been reported before, it has been difficult to dissociate the effects of other drugs.

In a case of cannabis-associated arteritis aspirin treatment resulted in revascularization [ ].

  • A 48-year-old woman developed necrosis of the right big toe and ultrasound showed complete occlusion of the large arteries below the knees bilaterally, but without atherosclerosis of the iliofemoral arteries, which might be expected in peripheral vascular disease. She stopped using marijuana and took aspirin 100 mg/day. Within 6 months all the arteries in the leg were patent and the toe had healed.

The authors suggested that aspirin could be effective in early intervention for cannabis-associated arteritis, making it important to distinguish arteritis from peripheral vascular disease.

Popliteal artery entrapment occurred in a patient with distal necrosis and cannabis-related arteritis, two rare or exceptional disorders that have never been described in association [ ].

  • A 19-year-old man developed necrosis in the distal third right toe, with loss of the popliteal and foot pulses. Arteriography showed posterior popliteal artery compression in the right leg and unusually poor distal vascularization in both legs. An MRI scan did not show a cyst and failed to identify the type of compression and the causal agent. Surgery showed that the patient had type III entrapment. Surprisingly, the pain failed to regress and the loss of distal pulses persisted despite a perfect result on the postoperative MRA scan. The patient then admitted consuming cannabis 10 times a day for 4 years, which suggested a Buerger-type arteritis related to cannabis consumption. A 21-day course of intravenous vasodilators caused the leg pain to disappear and the toe necrosis to regress. An MRA scan confirmed permanent occlusion of three arteries on the right side of the leg and the peroneal artery on the left side. Capillaroscopy excluded Buerger’s disease.

The authors suggested that popliteal artery entrapment in a young patient with non-specific symptoms should raise the suspicion of a cannabis-related lesion. Their review of literature suggested that this condition affects young patient and that complications secondary to popliteal artery entrapment did not occur in those who were under 38 years age.

Cardiac dysrhythmias

The dysrhythmogenic properties of cannabis appear to be influenced by the effects of tetrahydrocannabinol on action potential shortening and on vagal tone hyperstimulation. A case of Brugada-like syndrome has been reported [ ].

  • A healthy 19-year-old man suffered an attack of syncope lasting 2 minutes after heavy cannabis smoking. An electrocardiogram showed 2 mm ST segment elevation in leads V1 and V2. Two-dimensional echocardiography showed normal left ventricular function without any structural abnormalities. Investigation of vasovagal mediated syncope was negative. Urine and blood toxicology showed tetrahydrocannabinol. After resolution of the ST segment abnormalities, a procainamide induction test failed to elicit ST-T wave changes.

The authors suggested that the ST segment abnormalities may have been related to partial sodium channel opening secondary to marijuana.

Paroxysmal atrial fibrillation has been reported in two cases after marijuana use [ ].

  • A healthy 32-year-old doctor, who smoked marijuana 1–2 times a month, had paroxysmal tachycardia for several months. An electrocardiogram was normal and a Holter recording showed sinus rhythm with isolated supraventricular extra beats. He was treated with propranolol. He later secretly smoked marijuana while undergoing another Holter recording, which showed numerous episodes of paroxysmal atrial tachycardia and atrial fibrillation lasting up to 2 minutes. He abstained from marijuana for 12 months and maintained stable sinus rhythm.

  • A 24-year-old woman briefly lost consciousness and had nausea and vomiting several minutes after smoking marijuana. She had hyporeflexia, atrial fibrillation (maximum 140/minute with a pulse deficit), and a blood pressure of 130/80 mmHg. Echocardiography was unremarkable. Within 12 hours, after metoprolol, propafenone, and intravenous hydration with electrolytes, sinus rhythm was restored.

The authors discussed the possibility that Δ9-THC can cause intra-atrial re-entry by several mechanisms and thereby precipitate atrial fibrillation.

Sustained atrial fibrillation has also been attributed to marijuana [ ].

  • A 14-year-old African-American man with no cardiac history had palpitation and dizziness, resulting in a fall, within 1 hour of smoking marijuana. After vomiting several times he had a new sensation of skipped heartbeats. The only remarkable finding was a flow murmur. The electrocardiogram showed atrial fibrillation. Echocardiography was normal. Serum and urine toxicology showed cannabis. He was given digoxin, and about 12 hours later his cardiac rhythm converted to sinus rhythm. Digoxin was withdrawn. He abstained from marijuana over the next year and was symptom free.

The authors noted that marijuana’s catecholaminergic properties can affect autonomic control, vasomotor reflexes, and conduction-enhancement of perinodal fibers in cardiac muscle, and thus lead to an event such as this.

  • A 34-year-old man developed palpitation, shortness of breath, and chest pain. He had smoked a quarter to a half an ounce of marijuana per week and had taken it 3 hours before the incident. He had ventricular tachycardia at a rate of 200/minute with a right bundle branch block pattern. Electrical cardioversion restored sinus rhythm. Angiography showed a significant reduction in left anterior descending coronary artery flow rate, which was normalized by intra-arterial verapamil 200 micrograms.

The authors thought that marijuana may have enhanced triggered activity in the Purkinje fibers along with a reduction in coronary blood flow, perhaps through coronary spasm.

In terms of its potential for inducing cardiac dysrhythmias, cannabis is most likely to cause palpitation due to a dose-related sinus tachycardia. Other reported dysrhythmias include sinus bradycardia, second-degree atrioventricular block, and atrial fibrillation. Also reported are ventricular extra beats and other reversible electrocardiographic changes. Supraventricular tachycardia after the use of cannabis has been reported [ ].

  • A 35-year-old woman with a 1-month history of headaches was found to be hypertensive, with a blood pressure of 179/119 mmHg. She smoked 20 cigarettes a day and used cannabis infrequently. Her family history included hypertension. Electrocardiography suggested left ventricular hypertrophy but echocardiography was unremarkable. She was given amlodipine 10 mg/day and the blood pressure improved. While in the hospital, she smoked marijuana and about 30 minutes later developed palpitation, chest pain, and shortness of breath. The blood pressure was 233/120 mmHg and the pulse rate 150/minute. Electrocardiography showed atrial flutter with 2:1 atrioventricular block. Cardiac troponin was normal at 12 hours. Urine toxicology was positive for cannabis only. Two weeks later, while she was taking amlodipine 10 mg/day and atenolol 25 mg/day, her blood pressure was 117/85 mmHg.

The authors reviewed the biphasic effect of marijuana on the autonomic nervous system. At low to moderate doses it causes increased sympathetic activity, producing a tachycardia and increase in cardiac output; blood pressure therefore increases. At high doses it causes increased parasympathetic activity, leading to bradycardia and hypotension. They thought that this patient most probably had adrenergic atrial flutter.

Respiratory

Acute inhalation of marijuana or THC causes bronchodilatation, but with chronic use resistance in the bronchioles increases [ , ]. Prolonged use of cannabis by inhalation can cause chronic inflammatory changes in the bronchial tree, in part related to the inhalants that accompany the smoke. In some cases attacks of asthma and glottal and uvular angioedema can occur. Reduced respiratory gas exchange has been reported in long-term smokers, and under experimental conditions THC can depress respiratory function slightly and act as a respiratory irritant. In fact, chronic marijuana cigarette smoking and chronic tobacco cigarette smoking produce very similar changes, but these occur after smoking fewer cigarettes when marijuana is smoked, compared with tobacco-smoking. With marijuana inhalation, when a filter is never used, inhalation is deeper and the smoke is held in the lungs for longer than when smoking commercially produced tobacco-based cigarettes [ ]. There is therefore a greater build-up of carbon monoxide, reduction in carboxyhemoglobin saturation, and alveolar cellular irritation with depression of macrophages [ ]. Pneumothorax, pneumopericardium, and pneumomediastinum have been reported when positive pulmonary pressure is applied or a Valsalva maneuver used, as often happens [ , ].

Cannabis smoking can cause serious damage to the lungs [ ]. “Bong lung” is a term that is used to refer to a histological change that occurs in the lungs of chronic cannabis smokers, characteristic of irregular emphysema [ , ]. Patients with cannabis-induced recurrent pneumothorax often undergo resection of bullae. In Australia, the histopathology of resected lung was examined in 10 cannabis smokers, 5 heavy tobacco smokers, and 5 non-smokers. All marijuana smokers had irregular emphysema with cystic blebs and bullae in the lung apices. There was also massive accumulation of intra-alveolar pigmented histiocytes or “smoker’s macrophages” throughout the pulmonary parenchyma, but sparing of the peribronchioles, similar to desquamative interstitial pneumonia.

  • A 39-year-old man developed weight loss, fever, dry cough, and pleuritic chest pain. His cannabis and cigarette smoking history had started at age 12 and his current habit was 3 g of cannabis daily and 50 cigarette packs per year. A CT scan of the lung showed a pattern of large peripheral paraseptal bullae.

The authors compared this patient’s CT scan with one from a cigarette smoker. The second scan illustrated a strikingly different pattern of emphysema, with smaller panacinar bullae in a uniformly distributed centrilobular pattern. An explanation of the differences in lung findings due to cannabis and cigarettes would take into account a number of variables. Cannabis smoking requires longer inhalation and breath-holding time. Inhaled cannabis through a bong is at a higher temperature. A cannabis joint, which lacks a filter, also has a greater delivery of exposure.

Four men, who smoked both tobacco and marijuana, developed large, multiple, bilateral, peripheral bullae at their lung apices, with normal parenchymal tissue elsewhere [ ]. Three patients with large bullae in the upper lung lobe have been reported [ ]. All had been heavy marijuana smokers over 10–24 years. However, they all had at least nine pack-years of cigarette exposure and so marijuana may not have been the only cause of their lung bullae. Nevertheless, the authors recommended that all those who present with upper lung bullae should be screened for cannabis use.

While Δ9-THC may not contribute directly to lung bullae, it is possible that the respiratory dynamics of smoking the drug explains it. Typically, a draw on a marijuana joint has, on average, a depth of inspiration that is one-third greater, a volume two-thirds greater, and a breath-holding time four times longer than a draw on a cigarette. The marijuana joint lacks a filter tip, and the practice of smoking “leads to a fourfold greater delivery of tar and a five times greater increase in carboxyhemoglobin per cigarette smoked” [ ]. Smoking three to four joints of marijuana per day is reported to produce a symptom profile and damage to the respiratory airways similar to that caused by smoking 20 tobacco cigarettes daily.

In 10 marijuana smokers with respiratory problems (mean age 41 years, 8 men), who had smoked marijuana regularly for at least 12 months, bullous lung disease was identified by high-resolution CT scanning [ ]. Their presenting problems included dyspnea (n = 4), pneumothorax (n = 4), and lung infection (n = 2). In four patients the chest X-ray was normal; in five cases lung function tests were normal. The authors suggested that people who smoke cannabis present at a young age with significant respiratory problems and changes.

Cannabis smoking can cause pneumothorax [ ].

  • A 23-year-old man who had smoked cannabis regularly for about 10 years developed severe respiratory distress. He had bilateral pneumothoraces with complete collapse of the left lung.

No obvious reason for the problem was found and the authors suggested that coughing while breath-holding during cannabis inhalation had caused the problem.

Nervous system

Propriospinal myoclonus has been reported after cannabis use [ ].

  • A 25-year-old woman developed spinal myoclonus 18 months after having experienced acute-onset repetitive involuntary flexion and extension spasms of her trunk immediately after smoking cannabis. The jerks, which lasted 2–5 seconds, involved the trunk, neck, and to a lesser extent the limbs. The attacks occurred in clusters lasting up to 2 weeks and she was asymptomatic for 2–3 months between clusters. The myoclonus was not present during sleep. During a bout of jerks, myoclonus would occur every few minutes and continue for up to 9 hours, with associated fatigue and back pain. Neurological examination showed repetitive flexion jerks of the trunk with no other abnormal signs. An electroencephalogram, an MRI scan of the head and spine, and a full-length myelogram were all normal. Multi-channel surface electromyography with parallel frontal electroencephalography showed propriospinal myoclonus of mid-thoracic origin.

There have been no previous reports of propriospinal myoclonus precipitated by marijuana. The etiology was not clear but may have involved cannabinoid receptors located in the brain and spinal cord as well as the peripheral nervous system.

Amnesia

Transient global amnesia, an amnesia of sudden onset regarding events in the present and recent past, typically occurs in elderly people. Transient amnesia has been reported after marijuana use [ ].

  • A 40-year-old healthy man with a long history of cannabis use was hospitalized with an acute memory disturbance after smoking for several hours a strong type of marijuana called “superskunk.” After smoking, he had difficulty recollecting recent events and would ask the same questions repeatedly. While his routine laboratory results were within the reference ranges, his urine and blood toxic screens had very high concentrations of cannabinoids (and no other drugs). He was alert and oriented to his name, address, date, and place of birth, but could not recall his marital status, whether he had children, or the nature of his job. He was disoriented in time. He performed normally in tests of general cognitive functioning (for example Raven’s matrices, word fluency, Rey’s complex figure) and short-term memory (for example digit span, verbal cues), but showed severe impairment in verbal and non-verbal long-term components of anterograde memory tests. He had a severe retrograde memory defect mainly affecting autobiographical memory, with a temporal gradient such that remote facts were preserved. These memory impairments lasted 4 days and then rapidly improved, leaving amnesia for the acute episode. Electroencephalography during the amnestic episode was normal, except for brief trains of irregular slow activity in the frontal areas bilaterally. A SPECT scan of his brain was normal. A week later, repeat neuropsychological examination showed normal memory and a normal electroencephalogram and MRI scan of the brain with enhancement. One year later, he had stopped using marijuana and had no further amnestic episodes.

The authors found similarities between the memory disorder seen here and transient global amnesia (see above), which consists of anterograde amnesia and a variably graded retrograde amnesia. The authors stated that although memory impairment has been reported with marijuana before, it has never involved retrieval of already learned material. They wondered if the memory impairment was due to marijuana-induced changes in cerebral blood flow and ischemia through vasospasm. However, their SPECT data did not support this theory. They considered the possibility that cannabinoid receptors, which are dense in the hippocampus, could have been occupied by marijuana, resulting in such memory loss. They cautioned that the effects of marijuana on memory may be more severe than previously thought.

Transient global amnesia following accidental marijuana ingestion has been reported in a young boy [ ].

  • A 6-year-old boy accidentally became intoxicated with marijuana after eating cookies laced with marijuana. He developed retentive memory deficits of sudden onset, later diagnosed as transient global amnesia. He was anxious and had a tachycardia, fine tremors in the upper and lower limbs, and an ataxic gait. His CSF was unremarkable. He had cannabinoids in his urine. His memory returned to normal after 14 hours. His mother admitted baking marijuana cookies and leaving them out on the kitchen table. Up to 12 months later he had no memory of the episode.

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